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PubMed2001

Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine.

The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.

Azathioprine↗
PubMed1998

Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children's cancer group and pediatric oncology branch study.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 micromol*h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 micromol*h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P =.007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P =.043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

Administration, Oral↗
PubMed1965

INHIBITION OF PRUINE PHOSPHORIBOSYLTRANSFERASES OF EHRLICH ASCITES-TUMOUR CELLS BY 6-MERCAPTOPURINE.

1. The formation of adenosine 5'-phosphate, guanosine 5'-phosphate and inosine 5'-phosphate from [8-(14)C]adenine, [8-(14)C]guanine and [8-(14)C]hypoxanthine respectively in the presence of 5-phosphoribosyl pyrophosphate and an extract from Ehrlich ascites-tumour cells was assayed by a method involving liquid-scintillation counting of the radioactive nucleotides on diethylaminoethylcellulose paper. The results obtained with guanine were confirmed by a spectrophotometric assay which was also used to assay the conversion of 6-mercaptopurine and 5-phosphoribosyl pyrophosphate into 6-thioinosine 5'-phosphate in the presence of 6-mercaptopurine phosphoribosyltransferase from these cells. 2. At pH 7.8 and 25 degrees the Michaelis constants for adenine, guanine and hypoxanthine were 0.9 mum, 2.9 mum and 11.0 mum in the assay with radioactive purines; the Michaelis constant for guanine in the spectrophotometric assay was 2.6 mum. At pH 7.9 the Michaelis constant for 6-mercaptopurine was 10.9 mum. 3. 25 mum-6-Mercaptopurine did not inhibit adenine phosphoribosyltransferase. 6-Mercaptopurine is a competitive inhibitor of guanine phosphoribosyltransferase (K(i) 4.7 mum) and hypoxanthine phosphoribosyltransferase (K(i) 8.3 mum). Hypoxanthine is a competitive inhibitor of guanine phosphoribosyltransferase (K(i) 3.4 mum). 4. Differences in kinetic parameters and in the distribution of phosphoribosyltransferase activities after electrophoresis in starch gel indicate that different enzymes are involved in the conversion of adenine, guanine and hypoxanthine into their nucleotides. 5. From the low values of K(i) for 6-mercaptopurine, and from published evidence that ascites-tumour cells require supplies of purines from the host tissues, it is likely that inhibition of hypoxanthine and guanine phosphoribosyltransferases by free 6-mercaptopurine is involved in the biological activity of this drug.

Adenine↗
PubMed2000

Azathioprine or 6-mercaptopurine for inducing remission of Crohn's disease.

OBJECTIVES: To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease. SEARCH STRATEGY: Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched. SELECTION CRITERIA: Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView). MAIN RESULTS: The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14. REVIEWER'S CONCLUSIONS: Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.

Antimetabolites↗
PubMed1985

The effect of 6-mercaptopurine on natural killer-cell activities in Crohn's disease.

Crohn's disease patients on long-term 6-mercaptopurine therapy (more than 4 months) were evaluated for activity of peripheral blood natural killer cells. Natural killer-cell cytolytic activity against K-562 tumor-cell targets was examined, as was natural killer-cell suppression of lymphoblastoid B-cell antibody production. In addition, these patients were studied for their ability to generate antitetanus-specific IgG-antibody-producing lymphoblastoid B cells following in vivo booster immunization. Crohn's disease patients on 6-mercaptopurine therapy had significant reductions in peripheral blood natural killer-cell activity against K-562 targets compared to normals, disease controls, and Crohn's disease patients not on 6-mercaptopurine. Natural killer-cell suppression of lymphoblastoid B-cell antibody production was likewise decreased in 6-mercaptopurine-treated patients compared to normal controls. In contrast, the in vivo generated lymphoblastoid B-cell antibody responses of Crohn's disease patients on 6-mercaptopurine therapy were not decreased compared to normal, while Crohn's disease patients not on 6-mercaptopurine therapy had significantly impaired IgG antitetanus antibody responses. These findings suggest that 6-mercaptopurine therapy in Crohn's disease affects several lymphoid subpopulations, resulting in a decreased natural killer-cell cytotoxic activity against K-562 target cells and a decreased natural killer-cell ability to suppress lymphoblastoid B-cell antibody production, as well as an improved humoral immune response following tetanus toxoid booster immunization.

Adult↗
PubMed2003

Predictive factors of response of perianal Crohn's disease to azathioprine or 6-mercaptopurine.

PURPOSE: This study was designed to evaluate the predictive factors of response of perianal Crohn's disease to azathioprine or 6-mercaptopurine. METHODS: Ninety-four patients (65 females; mean age, 31 years) with active perianal Crohn's disease were treated with azathioprine or 6-mercaptopurine for more than 6 (median, 27) months (median azathioprine dose, 2 mg/kg/day). The evolution of perianal lesions during azathioprine or 6-mercaptopurine therapy was analyzed retrospectively. Patients who had a clear anatomic improvement (fistula closure, fissure healing, stricture dilatation) and who did not develop any perianal complications requiring an antibiotic course or surgical intervention were considered responders regarding their perianal disease. RESULTS: Three years after inclusion, the cumulative probabilities of remaining free of perianal complication and achieving a clear anatomic improvement were 0.47 (95 percent confidence interval, 0.36-0.58) and 0.4 (95 percent confidence interval, 0.29-0.53), respectively. On the whole, 27 patients (29 percent) were responders to azathioprine or 6-mercaptopurine therapy. The absence of fistula, duration of perianal disease shorter than 22 months, and aged 40 years or older at inclusion were three independent factors associated with response to azathioprine or 6-mercaptopurine therapy. There was no correlation between the response of perianal lesions and the achievement of intestinal remission with azathioprine or 6-mercaptopurine. CONCLUSION: One-third of patients with perianal lesions of Crohn's disease demonstrated a clear improvement during azathioprine or 6-mercaptopurine therapy. Patients aged 40 years or older with a recent perianal disease and without fistula were the best responders.

Adolescent↗
PubMed1988

Transport and metabolism of 6-thioguanine and 6-mercaptopurine in mouse small intestine.

1. The transport of 6-thioguanine and 6-mercaptopurine has been studied with isolated jejunal loops of mouse small intestine. H.p.l.c. was used to identify and quantify the thiopurines and their metabolites in the serosal secretions. 2. When the lumen of the intestinal loops contained either 6-thioguanine or 6-mercaptopurine at a concentration of 1 mmol/l, the concentration of unmetabolized drug in the serosal secretions reached a maximum of 0.13 +/- 0.02 mmol/l (mean +/- SEM). 3. Analysis of the serosal secretions from the perfusions with either of the drugs revealed the appearance of an unknown compound which had the characteristics of a thiopurine and the same time course of appearance as the unmetabolized drug. Thus 6-thioguanine and 6-mercaptopurine are significantly metabolized during absorption in mouse intestine. 4. The unknown compound was identified as 6-thiouric acid, and with 1 mmol/l 6-thioguanine or 6-mercaptopurine in the lumen the concentration of this metabolite in the serosal secretions rose to a maximum of 0.13 +/- 0.01 and 0.18 +/- 0.03 mmol/l, respectively. At luminal drug concentrations of 0.1 mmol/l, the metabolite accounted for approximately 90% of the serosal thiopurine. 5. After an initial lag period of 20 min, linear rates of appearance in the serosal secretions were obtained for both the unmetabolized drugs and 6-thiouric acid. 6. Addition of the xanthine oxidase inhibitor oxypurinol at a luminal concentration of 0.3 mmol/l prevented the formation of 6-thiouric acid from 6-thioguanine. However, the inhibitor reduced the rate of 6-thioguanine appearance in the serosal secretions by 50%. 7. The conversion of 6-mercaptopurine to 6-thiouric acid was prevented when allopurinol or oxypurinol were added to the lumen. At a luminal drug concentration of 1 mmol/l, allopurinol increased the rate at which 6-mercaptopurine appeared in the serosal secretions by 90% compared with an increase of only 50% with oxypurinol. 8. The transport of water and glucose by the mouse intestinal loops was unaffected by 6-thioguanine or the xanthine oxidase inhibitors. However, 6-mercaptopurine caused significant reductions in the rate of water transport (30%) and glucose transport (39%). These effects were observed at a luminal drug concentration of 0.1 mmol/l and there was no further increase at a drug concentration of 1 mmol/l.

Allopurinol↗
PubMed2005

6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine.

OBJECTIVE: Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable. MATERIAL AND METHODS: All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed. RESULTS: Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects. CONCLUSIONS: Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.

Adult↗
PubMed2003

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.

Administration, Oral↗
PubMed1997

Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia.

OBJECTIVE: The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881. RESULTS: After 1 month of oral treatment at a dose of 50 mg.m-2.day-1, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g.m-2 (bolus dose of 0.2 g.m-2 followed by an 8-h infusion of 0.8 g.m-2) in 11 patients: systemic clearance was 23.02 1.h-1, volume of distribution was 0.75 l.kg-1, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol x 10(8) packed RBC) or within 24 h of infusion (223 pmol x 10(8) packed RBC). The CSF concentration was 3.78 mumol.1(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16). In patients receiving the oral dose of 50-165 mg.m-2.day-1 of 6-mercaptopurine, CSF concentrations were below 0.18 mumol.1(-1), 1-24 h after drug intake (n = 67), and the CSF to plasma ratio was not calculated. CONCLUSION: Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n[symbol: see text]5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses.

Adolescent↗
PubMed1987

Tissue-specific gene expression results from a purine- and pyrimidine-free diet and 6-mercaptopurine in the rat small intestine and colon.

Dietary purines and pyrimidines are not considered to have a nutritional role, much less a direct effect on the functioning of the gastrointestinal tract. We found that a dramatic decrease in adult rat small intestinal and colonic total ribonucleic acid (RNA) results from the removal of dietary purines and pyrimidines or the administration of 6-mercaptopurine. Ribonucleic acid hybridization analysis indicated specific decrease of the messenger ribonucleic acid (mRNA) for the purine salvage enzymes hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase in the small intestine and proximal colon but not in the liver of animals fed a diet lacking purines and pyrimidines. Levels of intestinal and hepatic beta-actin mRNA transcripts were generally not depressed by either diet or by the administration of 6-mercaptopurine. Liver hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase mRNAs were unaffected by the change in diet but were lowered by the administration of 6-mercaptopurine. These data indicate that nutrition and 6-mercaptopurine affect both total RNA, and individual mRNA concentrations at specific sites in the gastrointestinal tract. These findings are of potentially great significance because the regulation of intestinal total RNA levels and purine salvage mRNAs by both 6-mercaptopurine and a purine- and pyrimidine-free diet suggests a potential mechanism by which dietary components differentially control specific proteins synthesized in the body. These findings may be related to the efficacy of 6-mercaptopurine as well as so-called elemental diets as therapeutic agents in chronic inflammatory bowel disease (i.e., Crohn's disease).

Adenine Phosphoribosyltransferase↗
PubMed1999

Methotrexate compared with mercaptopurine for early induced abortion.

OBJECTIVE: To compare the antimetabolites methotrexate and 6-mercaptopurine as single-agent medical abortifacients using clinical and immunohistochemical analyses. METHODS: Twenty-seven women with gestations less than 7 weeks from the last menstrual period (LMP) were randomized to receive intramuscular methotrexate, 50 mg/m2, or oral 6-mercaptopurine, 200 mg. Forty-six additional women received methotrexate after randomization was discontinued. Women returned at 2-week intervals. Those without fetal cardiac activity were followed until complete abortion. Those with fetal cardiac activity were considered failures and underwent suction abortions. Tissue collected at the time of suction abortion was analyzed with the cell-proliferation immunohistochemical assay Ki-67. RESULTS: All 12 women in the 6-mercaptopurine group had fetal cardiac activity at follow-up and underwent suction abortion; therefore, this arm of the study was discontinued. Six of the 61 women who received methotrexate had fetal cardiac activity at follow-up and also underwent suction abortion. Fetal cardiac activity was present after methotrexate in three of 55 women at less than 6 weeks from the LMP and in three of six between 6 and 7 weeks from the LMP (P < .01). Women who aborted after methotrexate started bleeding on day 19 (standard deviation [SD] 7.8), bled for 9 days (SD 4.0), and used minimal pain medications. Tissues exposed to methotrexate showed decreased Ki-67 activity compared with tissues exposed to 6-mercaptopurine (P = .003). CONCLUSION: In oral doses of 200 mg, 6-mercaptopurine did not induce early abortion. A single intramuscular dose of methotrexate used without prostaglandins induced abortion in most women at gestational ages of less than 6 weeks. Ki-67 activity was lower in a small sample of fetal tissues exposed to methotrexate than in tissues exposed to 6-mercaptopurine.

Abortifacient Agents↗
PubMed2006

Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial.

BACKGROUND: 6-mercaptopurine has been a standard component of long-term continuing treatment for childhood lymphoblastic leukaemia, whereas 6-thioguanine has been mainly used for intensification courses. Since preliminary data have shown that 6-thioguanine is more effective than 6-mercaptopurine, we compared the efficacy and toxicity of the two drugs for childhood lymphoblastic leukaemia. METHODS: Consecutive children with lymphoblastic leukaemia diagnosed in the UK and Ireland between April, 1997, and June, 2002, were randomly assigned either 6-thioguanine (750 patients) or 6-mercaptopurine (748 patients) during interim maintenance and continuing therapy. All patients received 6-thioguanine during intensification courses. We analysed event-free and overall survival on an intention-to-treat basis. We obtained toxicity data using an adverse-event reporting system, with follow-up questionnaires to seek detailed information for specific toxicities. This trial is registered with the International Standard Randomised Controlled Number 26727615 with the name ALL97. FINDINGS: After a median follow up of 6 years, there was no difference in event-free or overall survival between the two treatment groups. Although 6-thioguanine conferred a significantly lower risk of isolated CNS relapse than did 6-mercaptopurine (odds ratio [OR] 0.53, 95% CI 0.30-0.92, p=0.02), the benefit was offset by an increased risk of death in remission (2.22, 1.20-4.14, p=0.01), mainly due to infections during continuing therapy. Additionally, 95 patients developed veno-occlusive disease of the liver. Of these, 82 were randomly assigned 6-thioguanine, representing 11% of all 6-thioguanine recipients. On long-term follow-up, about 5% of 6-thioguanine recipients have evidence of non-cirrhotic portal hypertension due to periportal liver fibrosis or nodular regenerative hyperplasia. INTERPRETATION: Compared with 6-mercaptopurine, 6-thioguanine causes excess toxicity without an overall benefit. 6-mercaptopurine should remain the thiopurine of choice for continuing therapy of childhood lymphoblastic leukaemia.

Adolescent↗
PubMed2000

The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy.

INTRODUCTION: Azathioprine is a useful therapy in patients with inflammatory bowel disease that is difficult to control. However, 10% of patients are unable to tolerate azathioprine, and the best form of treatment for this group of patients is unknown. The azathioprine metabolite 6-mercaptopurine may be a useful therapy for these patients. AIM: To review our clinical experience of the use of the 6-mercaptopurine in inflammatory bowel disease patients who are intolerant of azathioprine. METHODS: All patients who were prescribed 6-mercaptopurine in a 2-year period were identified from pharmacy records. The case notes were reviewed and those who had previously been intolerant of azathioprine were included. RESULTS: A total of 19 with either ulcerative colitis and Crohn's disease were included. The reasons for discontinuing azathioprine were side-effects (13 patients), failure of efficacy (four patients) and leucopenia (two patients). Eleven of the 19 patients (68%) tolerated 6-mercaptopurine, including seven out of 13 patients (54%) who discontinued azathioprine due to side-effects. The length of follow-up of patients on 6-mercaptopurine was between 126 and 780 days (median 390 days). DISCUSSION: 6-mercaptopurine should be considered in patients with inflammatory bowel disease who require continuing immunosuppressive therapy, but are intolerant of azathioprine.

Adult↗
PubMed1999

Determination by capillary zone electrophoresis of mercaptopurine and thioguanine concentration in capsules for paediatric patients.

OBJECTIVE: Mercaptopurine monohydrate and thioguanine are two antineoplastic agents that inhibit purine metabolism. They are given by mouth in the treatment of acute leukaemias, usually for the maintenance of remission. In order to quantify these two antimetabolites into capsules for paediatric patients prepared in the pharmacy department, a capillary zone electrophoresis method (CZE) was developed. METHOD: The equipment and reagents used included: a P/ACE 5000 capillary electrophoresis system, a 37 cm x 75 microm silica capillary, a 22.2 mM borate buffer (pH 9.0), 5 s high pressure injections, direct UV detection at 280 nm, run 20 kV. Hypoxanthine was used as an internal standard. RESULTS: All compounds were separated in less than 3 min using a constant voltage of 20 kV. At a theoretical concentration of 100 microg/ml, the accuracy (average percentage of recovery = 98.9%, RSD = 0.45%, n = 6 for mercaptopurine and average percentage of recovery = 101.7%, RSD = 0.20%, n = 6 for thioguanine), the repeatability (RSD = 0.84%, n = 6 for mercaptopurine and RSD = 0.75%, n = 6 for thioguanine), the reproducibility (RSD = 0.58%, n = 18 for mercaptopurine and RSD = 1.55%, n = 18 for thioguanine) and the linearity of detection (range 50-150% of the studied concentration, r > 0.999 for mercaptopurine and r > 0.998 for thioguanine) were satisfactory. The capsule excipients did not interfere with quantification of the mercaptopurine or thioguanine peak. CONCLUSION: The two antineoplastic agents could be assayed rapidly by the same capillary zone electrophoretic method with acceptable accuracy and precision. This method is suitable for routine control of capsules prepared for paediatric patients.

Antimetabolites, Antineoplastic↗
PubMed2003

Identification of the antineoplastic agent 6-mercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1.

The purine anti-metabolite 6-mercaptopurine is one of the most widely used drugs for the treatment of acute childhood leukemia and chronic myelocytic leukemia. Developed in the 1950s, the drug is also being used as a treatment for inflammatory diseases such as Crohn's disease. The antiproliferative mechanism of action of this drug and other purine anti-metabolites has been demonstrated to be through inhibition of de novo purine synthesis and incorporation into nucleic acids. Despite the extensive clinical use and study of 6-mercaptopurine and other purine analogues, the cellular effects of these compounds remain relatively unknown. More recently, purine anti-metabolites have been shown to function as protein kinase inhibitors and to regulate gene expression. In an attempt to find small molecule regulators of the orphan nuclear receptor Nurr1, interestingly, we identified 6-mercaptopurine as a specific activator of this receptor. A detailed analysis of 6-mercaptopurine regulation of Nurr1 demonstrates that 6-mercaptopurine regulates Nurr1 through a region in the amino terminus. This activity can be inhibited by components of the purine biosynthesis pathway. These findings indicate that Nurr1 may play a role in mediating some of the antiproliferative effects of 6-mercaptopurine and potentially implicate Nurr1 as a molecular target for treatment of leukemias.

Amino Acid Sequence↗
PubMed1955

Antagonistic effects of 6-mercaptopurine and coenzyme A on mitochondria and mitosis in tissue culture.

The partial mitotic inhibition caused by 6-mercaptopurine in tissue cultures of Crocker mouse sarcoma 180 and embryonic mouse skin is blocked by co-enzyme A. 6-Mercaptopurine and coenzyme A also have opposite effects on mitochondrial morphology. Mitochondria in cells treated with 6-mercaptopurine become thin and fragmented. Coenzyme A blocks this effect, and alone coenzyme A makes for longer and thicker mitochondria. 6-Mercaptopurine inhibits lipogenesis in embryo skin fibroblasts, and this inhibition is partly counteracted by coenzyme A, which by itself makes for a greater accumulation of lipid droplets in the cytoplasm. It is suggested that at least one part of the action by which 6-mercaptopurine decreases mitotic incidence in tissue cultures may be an interference on the part of 6-mercaptopurine, acting as an antimetabolite of coenzyme A, in mitochondrial function related to cell division.

Animals↗
PubMed1997

Introduction of 6-mercaptopurine in Crohn's disease patients during the perioperative period: a preliminary evaluation of recurrence of disease.

BACKGROUND: Recurrence of Crohn's disease after surgery is a common occurrence, pointing to the need for a strategy to prevent recurrent disease. We report the postoperative course of 10 patients who required intestinal resections for complications related to Crohn's disease. METHODS: All patients had a Pediatric Crohn's Disease Activity Index score of 10 or greater. Among these patients, 5 began treatment with 6-mercaptopurine in the perioperative period. All 10 had received various combinations of prednisone and salicylate compounds. Patients who were given 6-mercaptopurine did not discontinue the medication until 2 years after the surgery. RESULTS: To date, none of the five patients who were placed on 6-mercaptopurine have had recurrence of their Crohn's disease (mean disease-free period 32.6 +/- 18.4 months). Among those five patients not receiving 6-mercaptopurine there have been three relapses (mean time to relapse 3.7 +/- 1.2 months). Log-rank sum analyses of Kaplan-Meier survival curves show benefit to patients receiving 6-mercaptopurine in preventing relapses after intestinal resection (p < 0.05). CONCLUSIONS: Although the underlying pathophysiologic reasons leading to the high relapse rate after intestinal surgery in Crohn's disease are unknown, we conclude that treatment with 6-mercaptopurine in the perioperative period may be warranted to help prevent the recurrence of Crohn's disease after surgery.

Adolescent↗